Biography

Dr. Wang received a B.S. in biology from the Massachusetts Institute of Technology and a Ph.D. in epidemiology from The Johns Hopkins Bloomberg School of Public Health. From 1998 to 2000, she served as an Epidemic Intelligence Service Officer at the Centers for Disease Control and Prevention. Dr. Wang joined the NCI in 2000. Her research focus includes understanding the molecular pathogenesis and genetic susceptibility of cervical cancer and non-Hodgkin lymphoma.

Research Interests

Genetic Susceptibility and Molecular Markers of Cancer Pathogenesis

We are conducting molecular epidemiology studies to identify genetic markers of susceptibility in the exposure-to-disease continuum, as well as biomarkers of cancer development and progression in two tumor systems: cervical neoplasia and non-Hodgkin's lymphoma. For both tumors, ongoing studies include investigations of markers of susceptibility with particular emphasis on immune and immune-related genes. In addition, identifying molecular markers of disease pathogenesis are underway utilizing novel biological methods, including cytogenetic techniques, gene expression via microarray technologies, and restriction landmark genome scanning.

Genetics of Cervical Neoplasia

Susceptibility Genes for HPV Infection and Cervical Cancer

While infection by human papillomavirus (HPV) is accepted as the central risk factor for cervical cancer, it is unlikely to be sufficient for developing cancer. Only a subset of HPV-infected individuals develop persistent infection, and of those, a subset develop low-grade lesions, and fewer develop high-grade lesions and subsequent cancer. These findings indicate that factors in addition to HPV infection are likely to be important determinants in cervical cancer carcinogenesis. Ongoing research includes investigating the role of specific genetic factors in determining HPV-persistence and subsequent progression of disease. Since genetic factors may modify HPV infection, our research includes efforts aimed at assessing genes that influence immune function. In three NCI-sponsored studies, including a population-based cohort of 10,000 women in Costa Rica, a population-based cohort of 24,000 women in Portland, Oregon, and a case-control study in the Eastern United States, we are examining the association between various polymorphic genes important to immune function, such as killer immunoglobulin receptors (KIRs) with cervical cancer. To enhance the number of cervical cancer cases and thus power for our genetic susceptibility studies, we have now completed the Genetic Supplementation Study (GSS) within the Guanaste Study. Also planned within the on-going HPV vaccine efficacy trial in Costa Rica are studies to assess the role of genetic factors in the heterogeneity of vaccine responses and in rapid onset disease.

Biomarkers of Risk for Progressive Cervical Neoplasia

To increase our understanding of the mechanisms involved in cervical carcinogenesis and to develop a new set of biomarkers that can distinguish those at highest risk of cervical cancer from those with benign infection, the Study to Understand Cervical Cancer Early Endpoints and Determinants (SUCCEED) was launched in November 2002 to comprehensively assesses biomarkers of risk for progressive cervical neoplasia. Employing an epidemiologic study design, we plan to identify, validate, and quantify the risk relationships of candidate biomarkers in cervical carcinogenesis. We are developing a comprehensive list of potential risk biomarkers via gene expression and microarray technology. By measuring gene expression profiles, we will gain a comprehensive in vivo picture of cervical neoplasia carcinogenesis. Candidate biomarkers will subsequently be validated for key outcomes related to progression or non-progression.

Using resources from on-going studies, we are also evaluating the validity of candidate markers such as p16INK4a and methylation events in tumor suppressor gene promoters via candidate gene approach and whole-genome scans including restriction landmark genome scanning (RLGS).

Genetics of Non-Hodgkin's Lymphoma

Susceptibility Genes for Non-Hodgkin's Lymphoma

We are currently evaluating the role of genetic polymorphisms in non-Hodgkin's lymphoma (NHL) susceptibility in the NCI-sponsored NHL multi-center case-control study in the United States (U.S.). While the major risk factors for NHL are not yet known, studies have consistently shown a strong relationship between factors that alter the immune system and NHL. We are therefore investigating candidate genes that are relevant to immune pathways hypothesized to play a role in NHL etiology. These include: (1) inflammatory and regulatory cytokines, (2) Th1/Th2 cytokines, (3) genes involved in innate immunity, and (4) chemokines. In addition, the role of polymorphisms in genes that metabolize or have a role in NHL-relevant environmental exposures are also being evaluated, including organophosphates, solvents and chemicals, organochlorines, and DNA repair capacity from chemical exposures.

Cytogenetic Biomarkers of Risk for Non-Hodgkin's Lymphoma

Traditionally, cytogenetic markers have been used as markers of early biologic effect in assessing carcinogenic exposures. However, recent cohort studies suggest that cytogenetic markers, i.e., chromosomal aberrations in peripheral lymphocytes, may be predictive of subsequent risk of cancer. If validated, the implications of cytogenetic markers serving as predictive markers of cancer could be substantial, especially if shown to be independent of exposure. We are therefore investigating the hypothesis that cytogenetic markers are indicative of cancer risk in the current on-going NCI-sponsored case-control study of NHL using classic cytogenetic techniques and fluorescent in situ hybridization (FISH) methods.

Keywords

• Molecular epidemiology, molecular pathology, genetic susceptibility, cervical neoplasia, human papillomavirus, non-Hodgkin lymphoma

Selected Publications

• Wang SS, Wheeler CM, Hildesheim A, Schiffman M, Herrero R, Bratti MC, Sherman ME, Alfaro M, Hutchinson ML, Morales J, Lorincz A, Burk RD, Carrington M, Erlich HA, Apple RJ. "Human leukocyte antigen class I and II alleles and risk of cervical neoplasia: results from a population-based study in Costa Rica.' J Infect Dis 2001; 184:1310-4.
• Wang SS, Hildesheim A, Gao X, Schiffman M, Herrero R, Bratti MC, Sherman ME, Barnes WA, Greenberg MD, McGowan L, Mortel R, Schwartz PE, Zaino RJ, Glass AG, Burk RD, Karacki P, Carrington M. "Comprehensive analysis of human leukocyte antigen (HLA) class I alleles and cervical neoplasia in three epidemiological studies." J Infect Dis 2002; 186(5):598-605.
• Wang SS, Schiffman M, Shields TS, Herrero R, Bratti C, Hildesheim A, Rodriguez AC, Hildesheim A, Burk R, Clayton B, Viscidi R. "Seroprevalence of human papillomavirus 16, 18, 31, 45, and 53 in a population-based cohort in Costa Rica." Br J Cancer 2003; 89:1248-1254.
• Wang S, Hildesheim A. "Genetics and HPV variants in cervical carcinoma." J Natl Cancer Inst 2003; 31:35-40.
• Sherman ME, Wang S, Tarone R, Rich L, Schiffman M. "Histopathologic Extent of Cervical Intraepithelial Neoplasia 3 Lesions in the Atypical Squamous Cells of Undetermined Significance Low-grade Squamous Intraepithelial Lesion Triage Study: Implications for Subject Safety and Lead-time Bias." Cancer Epidemiol Biomarkers Prev 2003; 12:372-379.
• Sherman ME, Wang SS, Wheeler C, Rich L, Gravitt PE, Schiffman M. "Determinants of human papillomavirus load among women with histologic CIN3: dominant impact of surrounding low-grade lesions." Cancer Epidem Biomarkers Prevention 2003; 12:1038-1044.
• Wang SS, Sherman ME, Lacey JV, Hildesheim A, Devesa S. "Incidence trends for cervical adenocarcinoma and squamous cell carcinoma among white and black women in the United States from 1976 through 2000." Cancer 2004; 100(5):1035-44.
• Wang SS, Trunk M, Schiffman M, Sherman ME, Herrero R, Burk R, Bratti C, Chen S, Rodriguez AC, Reichert A, von Knebel Doeberitz C, Ridder R, von Knebel Doeberitz M. "Validation of p16INK4a as a marker of oncogenic HPV infection in cervical biopsies from a population-based cohort in Costa Rica." Cancer Epidemiol Biomarkers Prev. 2004; 13(8):1355-1360.
• Wang SS, Schiffman M, Herrero R, Carreon J, Hildesheim A, Rodriguez AC, Bratti MC, Sherman ME, Morales J, Guillen D, Alfaro M, Clayman B, Burk RD, Viscidi RP. "Determinants of human papillomavirus 16 serological conversion, persistence, and clearance in a population-based cohort of 10,000 women in Costa Rica." Br J Cancer 2004; 91(4): 1269-74.
• Wang SS, Schiffman M. "Medication use, medical conditions and the risk of HPV infection and subsequent cervical intraepithelial neoplasia 3 (CIN3) among women with mild cytologic abnormalities." Cancer Epidemiol Biomarkers Prev. 2005; 14(2): 542-545
• Sherman ME, Wang SS, Carreon J, Devesa S. "Survival and mortality among women in the U.S. diagnosed with cervical carcinoma." Cancer 2005; 103(6):1258-1264.
• Carrington M, Wang SS, Martin M, Schiffman M, Herrero R, Rodriguez R, Gao X, Karacki P, Hildesheim A. "Hierarchy of Resistance to Cervical Neoplasia Mediated by Combinations of KIR and HLA Loci." J Exp Med 2005; 201:1069-1075.
• Wang SS, Dasgupta A, Sherman ME, Walker J, Zuna R, Sakoda L, Wacholder S, Schiffman M, Baker C. "Effects of topical applications during colposcopy on microarray gene expression patterns in cervix tissues." Diag Mol Path 2005; 14:59-64.
• Khan M, Partridge E, Wang SS, Schiffman M, for the ALTS Group. "Socioeconomic status and risk of cervical intraepithelial neoplasia grade 3 among oncogenic HPV DNA positive women with equivocal or mildly abnormal cytology." Cancer 2005; 103(12).
• Zuna R, Wang SS, Rosenthal D, Jeronimo J, Schiffman M, Solomon D. "Determinants of human papillomavirus (HPV) negative low grade squamous intraepithelial lesions (LSIL) in the ASCUS LSIL Triage Study (ALTS)." (In Press, Cancer Cytopathology)
• Zhang Y, Lan Q, Rothman N, Zhu Y, Zahm SH, Wang SS, Holford TR, Leaderer B, Boyle P, Zhang B, Zou K, Chanock S, Zheng T. "An exonic splicing polymorphism in the BCL6 gene and risk of non-Hodgkin lymphoma" (In Press, J Nat Cancer Inst)
• Hartge P, Wang S. "Overview of the etiology and epidemiology of lymphoma." In: Mauch PM, Armitage JO, Harris NL, Coiffier B, Dalla-Favera R. Non-Hodgkin's Lymphoma. Baltimore: Lippincott, Williams and Wilkens, 2004.

Collaborators

DCEG Collaborators

• Dalsu Baris, M.D., Neil Caporaso, M.D., M.P.H., Stephen Chanock, M.D., Nilanjan Chatterjee, Ph.D., Susan Devesa, Sc.D., Patricia Hartge, Sc.D., Allan Hildesheim, Ph.D., Qing Lan, M.D., M.P.H., Nathaniel Rothman, M.D., M.H.S., Mark Schiffman, M.D., M.P.H., Mark Sherman, M.D., Sholom Wacholder, Ph.D.

Other NCI Collaborators

• Carl Baker, M.D., Ph.D., Mary Carrington, Ph.D., Diane Solomon, M.D.

Other ScientificCollaborators

• Terence Dunn, Michael Gold, Rosemary Zuna, Joan Walker, Oklahoma University Health Sciences Center, Oklahoma City, OK
• Adi Gazdar, Ph.D., University of Texas at Southwestern, Dallas, TX
• Patti E. Gravitt, Ph.D., M.S., The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
• Rolando Herrero, M.D., Ministry of Health, San Jose, Costa Rica
• Christoph Plass, Ph.D., University of Ohio, Columbus, OH
• Janet Rader, M.D., Washington University, St. Louis, MO
• Dominic Smiraglia, Ph.D. Roswell Cancer Institute, Buffalo, NY
• Marcus Trunk, M.D., MTM Laboratories, Heidelberg, Germany
• Magnus von Knebel Doeberitz, Ph.D., University of Heidelberg, Germany